Preparation of isonicotinic acid and esters thereof



f the alkaline UnitedStates Patent;

PREPARATION ISGNICQTINIC ACID AND ESTERS THEREOF e Morton Harfenist, Flushing, .Kew Gardens, and William M. Flushing, N. Y., assignors'to Chas- Pfizer Abraham Bavley, Brooklyn,

Wilbur A. Lazier, lylcLamore,

& Co., Inc., Brooklyn, N. Y., a corporation of Dela ware No Drawing. Application April 1, 1952, Serial No. 279,946

3 Claims. (Cl. zed-29s This invention relates to an improvedprocess for preparing isonicotinic acid, and more particularly, to an improved process for converting a 2,6-dihalopyridine-4- carboxylic acid to isonicotinic acid by hydrogenolysis in the presence of a catalyst and recovering the isonicotinic acid in the form of its esters. 1

It is known that a 2,6-dihalopyridine-4-carboxylic acid, such as '2,6-dichloropyridine-4-catboxylic.acid, 1,-canybe converted to isonicotinic acid by'hydrogenolysis inthe presence of a hydrogenation catalyst. Howeven'the catalysts-heretofore employed for this purpose are ingeneral expensive, necessitating great care in handling to avoid costly losses, or require relatively highratios of catalystto 1 reactannwhich also increases the cost of employing them. It has nowbeen found that isonicotinic acidcan' be 'pre-j f pared in excellent by hydrogenolysis acid under superatmospheric pressure and at an-elevated temperature in the presence of a Raney nickel catalyst. It

has furtherbeen found that the isonicotinic acid canbe' vents as ethanol and the like. The 2,6-dihalopyridine-4- carboxylic acid, which can be present in concentrations far. above those hitherto employed, is solubilized by useof an alkaline material, such as an alkaline earth or alkali metal hydroxide, preferably sodium hydroxide, in an amount sufficient to form thecorresponding metal salt. An additional amount of the alkaline material is employed to maintain the reaction mixture under alkaline conditionsthroughout the hydrogenolysis, thereby taking up the hydrogen halide which is split 01f and preserving the acyields andwith a minimum of catalyst of a 2,6-dihalopyridine-4-carboxylic is preferred for reasons of- Patented Apr. 17, 1956 Afterthe 2,6-dihalopyridine-4-carboxylic acid has been dissolved, the nickel catalyst is added to the solution in preparation for the hydrogenolysis. The catalyst which has been found to be particularly effective for'the reaction is that known as Raney nickel, which is prepared by treating an alloy of aluminum and nickel in finely divided form with an alkali to dissolve out the aluminum, leaving the nickel in a porous and highly active state. Relatively large ratios of catalyst to the 2,6-dihalopyridine-4-carboxylic acid can be employed successfully, an amount of catalyst equal to or greater than the amount of 2,6-dihalopyridine- 4-carboxylic acid being quite efiective. However, it has been found that excellent yields can be obtained with as little nickel as 10 percent by weight of the 2,6-dihalopyridine-4-carboxylic acid on a dry basis, when using approximately 3 equivalents of alkaline material per equivalent of '2,6-dihalopyridine-4-carboxylic acid.

The hydrogenolysis is carried out within the temperature range of Soto-125 C. and at a pressure from 400 to 1000 pounds of hydrogen per square inch. The time of reaction may vary considerably, depending upon the'reaction conditions, -etc., but in general, from about 2 to 7 hours is V suflicient totcomplete the conversion to isonicotinic acid.

The reaction is terminated whenapproximately2 mols of hydrogen have been' reactedper mol :of 2,6-dihalo-- pyridine:4-carboxylic acid; Care should be taken to avoid I extreme'conditions, since saturaton of the ring might occur. w. v

Upon completion of the hydrogenolysis, the. cataly'st is filtered off, and the filtratecan be treated by known me'th ods to obtain isonicotinic acid. However, while itfis possible to recover the isonicotinc acid by conventional 7 methods of separation, there are certain dilficulties intivity of thecatalyst. A total amount of three equivalents l materiaI per -,equiv alent of 2,6 -dihalopyridine-4-carb0xylic acid is preferred to accomplish'both purposes. Thus, in thecase of sodium hydroxide,.about three mols of sodium hydroxide to one mol of 2,6-dihalo-v pyridine-4-carboxylic acid are employed for optimum results. With substantially larger or smaller amounts of the; alkaline material, the catalyst activity appears to become reduced, a factor which may adversely affect the yield of isonicotinic acid, depending of the catalyst used. However, when the preferred quantity of alkaline material is employed, it has been found possible to elfect the hydrogenolysis with much less catalyst than would otherwise be necessary, thereby providing substantial savings in cost.

upon the quantity and activity 0 V is complete.

volved. For example, when the filtrate is acidified with a suitable acid, such as hydrochloric acid, to dispose of any excess alkali and release the isonicotinic acid, the isonicotinic acid does not readily crystallize out of solutionor such crystallization as occurs is incomplete. Nevertheless, it has been found that the isonicotinic acid can conveniently be removed from the acidified solution by formation of an ester thereof with a lower alkanol, followed by separation of the ester by distillation. When an ester is desired, such a procedure results in higher yields, than can be obtained by first separating the isonicotinic acid, since all of the isonicotinic acid present in the solution is made available for esterification. Moreover, the esters are purified more readily and more economically than the solid isonicotinic acid. The esters so produced can be used as such or reconverted to isonicotinic acid by known methods. 1

Before esterification, the water should be removed from the reaction mixture obtained in the hydrogenation step.

This can be accomplished by evaporation and/or azeo v tropic distillation with suitable solvents, such as hydrocarbons', the higher ketones, and the like. Thereafter, the properalkanol is added to prepare the desired ester. Suitable alkanols include methyl, ethyl, propyl and butyl-alco-- hol. 'An esterification catalyst,1such as dry hydrogen chloride gas of sulfuric acid, is then added and the mixture refluxed for about two to five hours until the esterification The excess alcoholisthen reducedpressure, leaving a solid residue from which the desired ester is readily separatedin pure form by neutralization, solvent extraction'anddistillation.

' The invention is further illustrated by the following examples: V

Example I Ten grns. (0.052 mol) of 2,6-dichloropyridine-4-carboxylic acid were dissolved in 200 cc. of dilute sodium hydroxide solution containing 14.8 gms. (0.37 mol) sodium hydroxide. About 20 gms. of Raney nickel catalyst were removed under;

then. addedto form a suspension, which was transferred to a 300 cc. hydrogenationbomb. Hydrogen. wasthen.

surehfelkwithini 1. /1 hours to 2l 0:pounds per.-square inch andstaycdconstant for the remainder: ofthe four hour-- period. Upon cooling overnight; the pressuredropped to- 160 pounds per squareiach, givinga.total-pressure-drop of;3.40 pounds per squareinch .which indicated that 2 mols of. hydrogen per. mol. of 2,6-dichloropyridine-4-carboxylic acidiwere. taken up during the reaction. This was substantiated. by running. a chloride determination onthe resulting product; After filtering off andwashing thecatalyst' with water, the filtrate was acidified to a pH of 6:.-$. with.hydrochloric acidandconcentrated' to dryness under reduced; pressure atabouts 70 C; Theproduct was further; dried by addingia' mixture of ethanol and benzene anrbdistilling. off the mixture azeotropically under reduced pressure.

Two hundredcc. of ethanol werethen added-toform a suspension; of: isonicotinicacid; which was cooled while saturating withanexcessof dry hydrogen chloride gas-to catalyze. the esterification. The mixture was refluxed-for a-period; of. about 4% hours, followed-by removal of the excess;alcohol?under. reduced pressure. The solid-residueremainir'tgwas'thentakenuup in-about 200 .cc. of-waterand made; slightlyzalkaline with sodium-carbonate, whereupon the; ester was. released as, an: oil. After two-extractions withiehlonoform, the yield. of crude-ester: was found to-be 81%;. Distillationiof the crude ester resulted in-the pure colorless ethyl ester of isonicotinic acid, having a boiling pnintof. 116* C. atz24 mm. mercury. Theamountofester thus; obtained was. 5.81. gms., amounting to an overall" yield. of 74% Example 11 Twenty grams (0.104 mol) of 2,6-dichloropyridine,-4+ carboxylic acid were dissolved in 100 cc. of sodium hydroxide solution containing 29.6 grns. (0.74 mol) sodium hydroxide. About 4 gms. Raney nickel catalyst were then added, and the mixture subjected to hydrogenolysis in a 300 cc. hydrogenation bomb under an initial hydrogen pressure of 800 pounds per square inch and at a temperature ofabout 100 C., After 3 hours, the, totalzpressure; drop was only about 270 pounds. The addition, offlasecond4 gm. portion of fresh catalyst to the mixture, fol;

lowedby further subjection to hydrogen. under, thesame conditions for aperiod of about l2hours, resulted in; no.

further appreciable drop in pressure. The. total; pressure:

drop of270 pounds at 100 C. corresponds to a hydro,- gen uptake, of only 0.12. mol, or a conversion of 5819GT:- cent to isonicotini'c acid.

Example III Forty grams (0.208 mol) of 2,6-dichloropyridine-4.- carboxylicacid were dissolved in 200 cc. of sodium hydroxide solution containing 25.8 gms. (0.624 mol) of sQdi-. um hydroxide. To this were added4 gms. of Raney nickel, whereupon the mixture was shaken for 7 hours in a 480cc.

bomb under 800 pounds per square inch hydrogenprese a substantially colorless liquid having a boiling point of .12. 13. C. 211.22. mmsma cury. he. amcu tot. ster. thus obtained was 26.3 gms., equivalent to a yield of 83.7 percent.

It can readily be seen from Example I that a high ratio of nickel catalyst to the 2,61dichloropyridine4-carboxylic acid resultedin a, goodyield of isonicotinic acid (andthe ethyl ester); even though the hydrogenolysis was carried out in the presence of a large excess ofsodium hydroxide. Howeyenwhen the quantity of. catalyst wasreducedand a large excess of sodiumhydroxide still employed; as in Example II, the-hydrogenolysis failed to go to completion. On-the other'hand, with the preferred quantity of sodium hydroxide used in Example III, that is, 3 mols sodium hydroxide per mol of 2,6-dichloropyridine-4-carboxylic acid, substantially complete hydrogenolysis and excellent yields were obtained, although only 10 percent catalyst by weight of the 2,6-dichloropyridine-4-carboxylic acid was present during the reaction.

Thus; thisinvention provides an economical and efli'cient process for'preparing isonicotinic acid and its esters without'thedi'sadvantages which attendpriorart methods. The estersso'obtained are useful as intermediates in organic syntheses, particularly inthe preparation of isonicotinic acid hydrazide, which has shown utility in the treatment of tuberculosis;

Resort may be had to such modifications and equivalents as fall within the spirit ofthe invention and the scope of' the appended claims.

We claims 1a A processfor'preparing isonicotinic acidwhich comprises: subjecting a- 2,6edihalOPYI'idiDC4C3IbOXY1iC acid in an=aqueous-medium to hydrogenolysis under superatmospherio pressure" and at an elevated temperature, in the presence of a Raney nickel catalyst andabout three equivalentsof analkalinc material per equivalentoi 2,6-dihalopyridine-4 carboxylic acid, and terminating the reaction whenrapproximately twcmolsof hydrogen have been rcacted pen-molof 2,6-dihalopyridine-4-carboxylic acid:

2. A process for preparing-isonicotinic acidwhich comprises. subjecting 2,6-dichloropyridine-4-carboxylic acid, in antaqueousmedium to hydrogenolysis-under superatmospheric pressure and at a temperature-from about 50 to 125 C. in the'presence of a Raney nickel catalyst and about three equivalentsof analkaline material per equivalent of the carboxylic acid, and terminating the reaction when approximately two mols of hydrogen have been reacted per mol of 2,6-dichloropyridine- -carboxylic acid:

3-'.. A.- processfor preparing isonicotinic acid which comprises: subjecting: an aqueous solution of one mol of 2;6- dichlorzopyridine-4-carboxylic acid'per three mols of sodium. hydroxide to hydrogenolysis at a pressure of from about-400 to 1000 pounds per square inch and at a temperature from aboutS'O-to 125 C. in the presence of approximately: 10% of a Raney nickel catalystby weight of the carboxylic acid, and terminating the reaction when approximately two mols'ofhydrogen have been reacted per mob of 2 ,6-dichloropyridine-4-carboxylic acid. 

1. A PROCESS FOR PREPARING ISONICOTINIC ACID WHICH COMPRISES SUBJECTING A 2,6-DIHALOPYRIDINE-4-CARBOXYLIC ACID IN AN AQUEOUS MEDIUM TO HYDROGENOLYSIS UNDER SUPERATMOSPHERIC PRESSURE AND AT AN ELEVATED TEMPERATURE, IN THE PRESENCE OF A RANEY NICKEL CATALYST AND ABOUT THREE EQUIVALENTS OF AN ALKALINE MATERIAL PER EQUIVALENT OF 2,6-DIHALOPYRIDINE-4-CARBOXYLIC ACID, AND TERMINATING THE REACTION WHEN APPROXOMATELY TWO MOLS OF HYDROGEN HAVE BEEN REACTED PER MOL OF 2,6-DIHALOPYRIDINE-4-CARBOXYLIC ACID. 